This proposal responds to Research Topics 6.2., "Hormonal changes associated with increased risk for peri-and postmenopausal health problems," and 17, "Basic underlying mechanisms of musculoskeletal aging." The aim of the proposed study is to determine whether estrogen is chondroprotective or chondrodestructive, specifically with regard to the development or prevention of arthritis. In addition to estrogen, we will also examine the effects on cartilage of the specific estrogen receptor modulator (SERM) raloxifene, currently used in lieu of estrogen replacement therapy as a preventive and treatment for the postmenopausal patient population at risk for bone loss.This same population has an increased incidence of osteoarthritis (OA) with advancing age. It is therefore important to study the effects of this SERM alongside those of estrogen. The central hypothesis of this proposal is that estrogen has a positive effect on human chondrocyte metabolism and therefore helps to prevent degenerative arthritis. To establish this, we propose to examine the effects of estrogen and raloxifene in vitro on markers of cartilage metabolism and degradation. Real-time PCR will be used to quantitatively determine mRNA levels of these markers. Anabolic markers to be examined are type II collagen, cartilage oligomeric matrix protein, and aggrecan; catabolic markers will include interleukin-1 (IL-1) and matrix metalloproteinase-13. Chondrocytes will be grown in three-dimensional culture conditions in order to closely mimic the natural state. In addition, an exogenous catabolic mediator, IL-1, will be separately added to the estrogen and raloxifene cultures to determine whether estrogen or raloxifene can block IL-l-induced degradation of cartilage. The wide use of estrogen in the OA population makes it extremely important to elucidate whether estrogen and its related SERM raloxifene promote cartilage homeostasis or contribute to its degradation. The inconclusive and contradictory data from human and animal studies render the proposed studies highly significant.